The present invention provides novel organic compounds. In particular, this invention relates to substituted imidazoles and substituted 1,2,4-triazoles.
The present invention also relates to novel methods for the synthesis and use of the novel organic compounds disclosed herein. The specification particularly relates to novel organic compounds for use as antiallergy agents, whereby they prevent the symptoms manifest in such states as asthma, seasonal pollinosis, allergic rhinitis, urticaria, allergic conjunctivitis, food allergy, and anaphylactoid reactions of a sensitized animal, especially man. Some of the novel compounds herein described also exhibit antihypertensive activity as well as antiallergy activity, and as such are useful in the treatment of hypertension.
Allergy is a condition whose chief manifestation is an allergic hypersensitivity reaction (AHR). AHR's are broad in their symptomology. The symptoms may include dermatitis, lacrimation, nasal discharge, cough, sneezing, nausea, vomiting, diarrhea, difficulty in breathing, pain, inflammation, and, in severe cases, anaphylactic shock, circulatory collapse, and even death. This manifestation is found in animals suffering from bronchial asthma, seasonal pollinosis (e.g., hayfever), allergic rhinitis, urticaria, allergic conjunctivitis, food allergies, and anaphylactoid reactions. The substances most frequently responsible for the clinical manifestations of AHR are plant pollen, animal feathers and danders, dust, milk, and wheat, whether inhaled or ingested.
AHR's are found in man as well as other animals. In an AHR an antibody (reagin in man) influences the cell membrane of a mast cell by reacting with an antigen, to initiate reactions within the mast cell which ultimately causes release of mediator (bioactive amine) such as bradykinin, slow reacting substance A (SRS-A), histamine, serotonin (5HT), possibly some prostaglandins, and possibly other unknown substances. The mediator is released from the mast cell where it attaches to suitable receptor sites (e.g., on smooth muscle) resulting in AHR attack symptoms. Various methods are used to relieve the symptoms of AHR including (1) avoiding attack by the antigen, (2) blocking production of antibody with an immunosuppresant, (3) blocking the receptor sites of the mediator, e.g., antihistamine, (4) using of bronchodilators, and (5) blocking reaction of antibody with the mast cell.
Hypertension is a condition which is often characterized by the arterioles exhibiting abnormal resistance to the flow of blood and is usually associated with an abnormal increase in systolic, diastolic, and mean arterial blood pressures. Arterial pressure is the product of cardiac output times the total peripheral resistance. An increase in either of these two factors therefore can cause hypertension. However, in most types of hypertension one finds the total peripheral resistance is greatly increased while the cardiac output is near to normal. Disease states exhibiting hypertension include renal hypertension, Goldblatt's hypertension, tumor-induced hypertension, and essential hypertension where etiology is unknown. Elevation of blood pressure has been induced in animals through the central nervous system, by neurogenic, renal and adrenal mechanisms, by ingestion of large amounts of sodium chloride, as well as by administration of certain drugs. Although all these mechanisms may play a part, heredity is a predisposing factor, suggesting a genetic contribution of some kind. Irrespective of the etiology of the condition, the elevated pressure per se accelerates a number of degenerative processes that shorten life expectancy. See Goodman and Gillman: The Pharmacological Basis of Therapeutics, 4th ed., 728-744 (1970 ).
Treatment of hypertension may be by treatment of the etiology of the hypertension or by the introduction of drugs that exhibit a direct effect on blood pressure. A patient who would be considered for treatment with pharmacologic agents is readily diagnosed by an attending physician. Indications for pharmacologic treatment include conditions where the patient has malignant hypertension, where the diastolic pressure is persistently above 95 mm Hg or where there is vascular disease related to the hypertensive state. These states may be readily determined by an attending physician of ordinary skill, See the Merck Manual 12th ed. 465-471 (1972).
Various imidazoles and 1,2,4-triazoles are well known in the prior art. These compounds have been described as useful for a wide range of uses. Such known imidazole compounds include 1,2,4,5-tetrasubstituted imidazoles useful as hypotensive, antitumor, antiviral, antiinflammatory agents, and as protective agents against, cerebral anoxia or hypoxia such as are described in British Pat. No. 2,016,011 (abstracted in Derwent Farmdoc CPI no. 68606B/38). French Pat. No. 2,132,632 (abstracted in Derwent Farmdoc CPI No. 10105U-B), U.S. Pat. No. 3,651,080, and Belgian Patent 810,117 (abstracted in Farmdoc CPI No. 41717V/23); 1-substituted imidazoles for use in treating inflammation, hypertension, thrombosis and asthma such as described in Japanese Patent Application 109974 (abstracted in Derwent Farmdoc CPI No. 72897B/40); 1,2-di-substituted-4-haloimidazoles-5-acetic acid derivatives for use as diuretics and hypotensives, as described in U.S. Pat. No. 4,207,324; and 1,4,5-trisubstituted imidazoles useful as antiallergic and hypotensive agent such as described in British Pat. No. 1,134,580. Known 1,2,4-triazole compounds include 1,3,5-trisubstituted 1,2,4-triazoles useful as: antiasthma and antiallergic agents as described in Netherlands Patent Application 06067 (abstracted in Derwent Farmdoc CPI No. 86573V/50); antihyperuricacidemic, diuretic, and hypotensive agents as described in U.S. Pat. No. 4,102,889 and U.S. Pat. No. 4,111,944; and as antiinflammatory agents as described in Belgian Pat. No. 875846 (abstracted in Derwent Farmdoc CPI No. 77110B/44). 3-substituted triazoles useful as hypotensives are also known such as described in Belgian Pat. No. 856356 (abstracted in Derwent Farmdoc CPI No. 02073A/02).